We documented somatostatin receptors type 2 (SSTR2) expression in thyroid cancer by the analysis of RNA seq data of 507 patients with papillary thyroid cancer enrolled in Thyroid Cancer Genome Atlas (TCGA) and showed higher expression of SSTR2 in tumor vs normal thyroid tissue (p=0.003). Immunohistochemical staining of 64 thyroid cancer tissue samples revealed high SSTR2 expression in 61% of thyroid cancer samples. We have utilized in vitro models of human papillary and follicular thyroid cancer and documented a moderate expression of SSTR2 in examined human thyroid cancer cell lines. We have shown that expression of SSTR2 is controlled by epigenetic mechanisms and treatment with certain pharmacological agents involved in epigenetic regulation leads to overexpression of SSTR2 in vitro. We developed a metastatic mouse model using immunocompromised mice developing lung and liver metastases after tail vein injection of human thyroid cancer cells. We showed a moderate level of radiolabeled SSTR2 analogs uptake in metastatic lesions as documented by PET/CT imaging in this model.These preliminary data indicate that (1) SSTR2 are expressed in thyroid cancer, (2) expression of SSTR2 could be increased by pharmacological agents involved in epigenetic modulation (3) SSTR2 based imaging and treatment can be tested in an established thyroid cancer metastatic mouse model that we have developed. Our preliminary results will form a basis for a phase 2 clinical trial involving 30 metastatic thyroid cancer patients, whose tumors are radioactive iodine refractory, but SSTR2 analogs-avid, utilizing the most effective therapeutic regimen from in vivo model.